Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal neovascularization

Retinal vasculogenesis and ischemic retinopathies provide good model system s for study of vascular development and neovascularization (NV), respective ly. Vascular endothelial cell growth factor (VEGF) has been implicated in t he pathogenesis of retinal vasculogenesis and in the development of retinal NV in ischemic retinopathies, However, insulin-like growth factor-I and po ssibly other growth factors also participate in the development of retinal NV and intraocular injections of VEGF antagonists only partially inhibit re tinal NV. One possible conclusion from these studies is that it is necessar y to block other growth factors in addition to VEGF to achieve complete inh ibition of retinal NV. We recently demonstrated that a partially selective kinase inhibitor, PKC412, that blocks phosphorylation by VEGF and platelet- derived growth factor (PDGF) receptors and several isoforms of protein kina se C (PKC), completely inhibits retinal NV. In this study, we have used thr ee additional selective kinase inhibitors with different selectivity profil es to explore the signaling pathways involved in retinal NV. PTK787, a drug that blocks phosphorylation by VEGF and PDGF receptors, but not PKC, compl etely inhibited retinal NV in murine oxygen-induced ischemic retinopathy an d partially inhibited retinal vascularization during development. CGP 57148 and CGP 53716, two drugs that block phosphorylation by PDGF receptors, but not VEGF receptors, had no significant effect on retinal NV, These data an d our previously published study suggest that regardless of contributions b y other growth factors, VEGF signaling plays a critical role in the pathoge nesis of retinal NV. Inhibition of VEGF receptor kinase activity completely blocks retinal NV and is an excellent target for treatment of proliferativ e diabetic retinopathy and other ischemic retinopathies.